Recent advances in cardiovascular stent for treatment of in-stent restenosis: Mechanisms and strategies

Major reactive oxygen species (ROS)-producing systems in vascular wall include NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase, xanthine oxidase, the mitochondrial electron transport chain, and uncoupled endothelial nitric oxide (NO) synthase. ROS at moderate concentrations have important signaling roles under physiological conditions. Excessive or sustained ROS production, however, when exceeding the available antioxidant defense systems, leads to oxidative stress. Animal studies have provided compelling evidence demonstrating the roles of vascular oxidative stress and NO in atherosclerosis. All established cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, and smoking enhance ROS generation and decrease endothelial NO production. Key molecular events in atherogenesis such as oxidative modification of lipoproteins and phospholipids, endothelial cell activation, and macrophage infiltration/activation are facilitated by vascular oxidative stress and inhibited by endothelial NO. Atherosclerosis develops preferentially in vascular regions with disturbed blood flow (arches, branches, and bifurcations). The fact that these sites are associated with enhanced oxidative stress and reduced endothelial NO production is a further indication for the roles of ROS and NO in atherosclerosis. Therefore, prevention of vascular oxidative stress and improvement of endothelial NO production represent reasonable therapeutic strategies in addition to the treatment of established risk factors (hypercholesterolemia, hypertension, and diabetes mellitus).

During the past two decades, nitric oxide (NO) has been recognized as one of the most versatile players in the immune system. It is involved in the pathogenesis and control of infectious diseases, tumors, autoimmune processes and chronic degenerative diseases. Because of its variety of reaction partners (DNA, proteins, low-molecular weight thiols, prosthetic groups, reactive oxygen intermediates), its widespread production (by three different NO synthases (NOS) and the fact that its activity is strongly influenced by its concentration, NO continues to surprise and perplex immunologists. Today, there is no simple, uniform picture of the function of NO in the immune system. Protective and toxic effects of NO are frequently seen in parallel. Its striking inter- and intracellular signaling capacity makes it extremely difficult to predict the effect of NOS inhibitors and NO donors, which still hampers therapeutic applications.

Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis.